Prostate cancer (PCA) is the most common malignancy and age-related cause of cancer death worldwide. Apart from lung cancer, PCA is the most common form of cancer in men and the second leading cause of death in American men. In the United States in 2008, it was estimated that 186,320 new cases of prostate cancer would be diagnosed and about 28,660 men would die of this disease, with African American men and Jamaican men of African decent having the highest incidence rates in the world (American Cancer Society—Cancer Facts and Figures 2008).
Androgens play an important role in the development, growth, and progression of PCA (McConnell, J. D., Urol. Clin. North Am., 1991, 18: 1-13), with the two most important androgens in this regard being testosterone (T), 90% of which is synthesized by the testes, and the rest (10%) is synthesized by the adrenal glands, and the more potent androgen, dihydrotestosterone (DHT), to which testosterone is converted by the enzyme steroid, 5α-reductase, that is localized primarily in the prostate (Bruchovsky, N. and Wilson, J. D., J. Biol. Chem., 1968, 243, 2012-2021).
Huggins et al. introduced androgen deprivation as a therapy for advanced and metastatic PCA in 1941 (Huggins, C., Stephens, R. C. and Hudges, C. V., Arch. Surg., 1941, 43, 209-212) and since then, androgen ablation therapy has been shown to produce the most beneficial responses in multiple settings in PCA patients (Denmeade, S. R. and Isaacs, J. T., Nature Rev. Cancer, 2002, 2: 389-396). Orchiectomy (either surgical or medical with a GnRH agonist), which reduces or eliminates androgen production by the testes, but does not affect androgen synthesis in the adrenal glands, is the standard treatment option for most prostate cancer patients. Several studies have reported that a combination therapy of orchiectomy with antiandrogens, to inhibit the action of adrenal androgens, significantly prolongs the survival of PCA patients (Crawford, E. D. et al, New Engl. J. Med., 1989, 321, 419-424; Crawford, E. D. and Allen, J. A., J. Urol., 1992, 147: 417A; and Denis, L., Prostate, 1994, 5 (Suppl.), 17s-22s).
In a recent featured article by Mohler and colleagues (Mohler, J. L. et al., Clin. Cancer Res., 2004, 10, 440-448), it was clearly demonstrated that testosterone and dihydrotestosterone occur in recurrent PCA tissues at levels sufficient to activate androgen receptors. In addition, using microarray-based profiling of isogenic PCA xenograft models, the Sawyer group (Chen, C. D. et al., Nat. Med., 2004, 10, 33-39) found that a modest increase in the androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. Potent and specific compounds that inhibit androgen synthesis in the testes, adrenals, and other tissue may be more effective for the treatment of PCA (Njar, V. C. O. and Brodie, A. M. H., Current Pharm. Design, 1999, 5: 163-180).
In the testes and adrenal glands, the last step in the biosynthesis of testosterone involves two key reactions, which act sequentially, and are both catalyzed by a single enzyme, the cytochrome P450 monooxygenase 17α-hydroxylase/17,20-lyase (CYP17; Hall, P. F., J. Steroid Biochem. Molec. Biol., 1991, 40, 527-532). Ketoconazole, an antifungal agent that also inhibits P450 enzymes, is, in addition, a modest CYP17 inhibitor, and has been used clinically for the treatment of PCA (Trachtenberg, J, et al., Urol. 1983, 130, 152-153). It is reported that careful scheduling of treatment can produce prolonged responses in otherwise castrate-resistant prostate cancer patients (Muscato, J. J. et al., Proc. Am. Assoc. Cancer Res., 1994, 13: 22 (Abstract)). Further, ketoconazole was found to retain activity in advanced PCA patients with progression, despite flutamide withdrawal (Small, E. J. et al., J. Urol., 1997, 157, 1204-1207). Although, the drug has now been withdrawn from use because of liver toxicity and other side effects, the ketoconazole results suggest that more potent and selective inhibitors of CYP17 could provide useful agents for treating this disease, even in advanced stages and in some patients who may appear to be hormone refractory.
A variety of potent steroidal and non-steroidal inhibitors of CYP17 have been reported and some have been shown to be potent inhibitors of testosterone production in rodent models. Recently, Jarman and colleagues have described the hormonal impact of their most potent CYP17 inhibitor, abiraterone, in patients with prostate cancer (O'Donnell, A. et al., Br. J. Cancer, 2004, 90: 2317-2325). Some potent CYP17 inhibitors have been shown to also inhibit 5α-reductase and/or be potent antiandrogens with potent antitumor activity in animal models (Long, B. J. et al., Cancer Res., 2000, 60, 6630-6640).
Additional background of the invention is contained in U.S. Pat. No. 5,604,213 (Barrie et al); U.S. Pat. No. 5,994,335 (Brodie et al); U.S. Pat. No. 6,200,965 (Brodie et al); and U.S. Pat. No. 6,444,683 (Brodie et al), each of which is incorporated by reference in its entirety.
Recent publications from Barrie et al. and Njar et al. teach a class of potent steroidal CYP17 inhibitors/antiandrogens, 17-pyridines, 17-benzoazoles, 17-pyrimidinoazoles and 17-diazines, that are particularly potent as inhibitors of the human CYP17 enzyme. Particularly-potent CYP17 inhibitors include 3β-hydroxy-17-(pyrid-3-yl)androsta-5,16-diene (abiraterone), 3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Compound 1), 17-(1H-benzimidazole-1-yl)androsta-4,16-diene-3-one (Compound 2) and 3β-hydroxy-17-(5′-pyrimidyl)androsta-5,16-diene (Compound 3), with IC50 values of 3-6, 50, 915, and 500 nM, respectively.

Compounds 1, 2, and 3 were effective at competing with the binding of 3H-R1881 (methyltrienolone, a stable synthetic androgen) to both the mutant and LNCaP AR and the wild-type AR, but with a 2.2- to 5-fold higher binding efficiency to the latter. Compounds 1 and 2 were also shown to be potent pure AR antagonists, and cell growth studies have shown that they also inhibit the growth of DHT-stimulated LNCaP and LAPC4 prostate cancer cells, with IC50 values in the low micromolar range (i.e., <10 μM). Their inhibitory potencies were comparable to that of casodex, but remarkably superior to that of flutamide. The pharmacokinetics of compounds 1 and 2 in mice showed that following s.c. administration of 50 mg/kg of compounds 1 and 2, peak plasma levels of 16.82 and 5.15 ng/mL, respectively, occurred after 30-to-60 minutes, both compounds were cleared rapidly from plasma (terminal half-lives of 44.17 and 39.93 min, respectively) and neither was detectable at 8 hours.
Compound 1 was rapidly converted into a metabolite, tentatively identified as 17-(1H-benzimidazol-1-yl)androsta-3-one. When tested in vivo, compound 1 proved to be very effective at inhibiting the growth of androgen-dependent LAPC4 human prostate tumor xenograft, while compound 2 was ineffective. Administration of compound 1 (50 mg/kg, twice daily) resulted in a 93.8% reduction (P=0.00065) in the mean final tumor volume compared with controls, and it was also significantly more effective than castration. This was the first example of an anti-hormonal agent (an inhibitor of androgen synthesis (CYP17 inhibitor)/antiandrogen) that is significantly more effective than castration in suppression of androgen-dependent prostate tumor growth. In view of these impressive anti-cancer properties, compound 1 and analogs may be used for the treatment of urogenital and/or androgen-related cancers, diseases and/or conditions, including but not limited to, human prostate cancer, as well as breast cancer, ovarian cancer, and other urogenital cancers.